In DIC, microthrombi are formed in microvasculature, in the presence of a severe underlying disease. The microthrombi damage the microcirculation and cause organ dysfunction or a bleeding tendency. The following three failures or reactions are observed in DIC:
(1) The microthrombus formation causes a microcirculatory failure, and a variety of organs fall into dysfunction due to ischemia.
(2) The microthrombus formation promotes a consumption coagulopathy, that is, an increase in tissue factor production on the surface of endothelial cells leads to activation of an extrinsic coagulation pathway. Further, coagulation factors and platelets are consumed, and a bleeding tendency occurs.(3) Hyperfibrinolysis, that is, the fibrinolytic system activated due to the activation of coagulation, generates plasmin, which degrades fibrin. When the α2-plasmin inhibitor (α2PI), which inhibits plasmin, is consumed and decreased to less than 60% of the normal level, fibrin is degraded by the plasmin and a bleeding tendency occurs.
DIC is mainly characterized by the microthrombus formation caused by the abnormal and continuous activation of coagulation, but the fibrinolytic system is also activated. The balance of coagulation and fibrinolysis varies in accordance with underlying diseases or cases. As such cases, a case in which coagulation is remarkably activated, but the fibrinolytic system is suppressed, and a case in which both the coagulation and fibrinolytic systems are remarkably activated, are known. The former is designated coagulation-dominant DIC, and the latter is coagulation-suppressed DIC. Coagulation-dominant DIC is often accompanied by infections, particularly sepsis, and organ failure is often observed as a clinical symptom in patients with coagulation-dominant DIC. In patients with coagulation-suppressed DIC, FDPs (Fibrin degradation products) and PIC (Plasmin/plasmin inhibitor complex), which are fibrinolytic markers, are remarkably increased, and bleeding is often observed. The underlying disease thereof is acute promyelocytic leukemia.
Since a delayed treatment for DIC would directly lead to death, DIC is an urgent disease requiring an early diagnosis and an early treatment. Diagnosis of DIC is now carried out in accordance with the diagnostic criteria for DIC, established by the Ministry of Health and Welfare (Japan). In these diagnostic criteria, DIC is judged by scoring each value of 1) the presence or absence of organ failure, 2) the platelet count, 3) FDPs, 4) fibrinogen, and 5) the PT ratio (prothrombin time ratio). The diagnostic criteria are suitable for a definitive diagnosis of DIC, but are not suitable for an early diagnosis of DIC. Where a clinical treatment of DIC is carried out in accordance with the diagnosis criteria, there are many cases in which DIC is at such an advanced stage that it is too late. Further, there are not a few cases, in the clinical field, where it is difficult to carry out a differentiation as to whether or not a decreased platelet count is caused by DIC. Examples of conditions or diseases with such a decreased platelet count include, for example, a condition accompanied by myelosuppression (such as drugs, viral infections, blood diseases caused dyshemopoiesis, cirrhosis, hepatic insufficiency, thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS), and excess pleural effusion or ascites. These conditions or diseases are sometimes accompanied by elevated FDPs and/or elevated D-dimer as well as decreased platelets, and it becomes more difficult to carry out a differentiation of DIC.
As a treatment for DIC, low-molecular-weight heparin or antithrombin III is administered, to suppress the multiple formations of thrombi in blood vessels and inhibit the progression of a consumption coagulopathy. To a patient suffering from coagulation-suppressed DIC, gabexate mesilate having an antithrombin activity and an antifibrinolytic effect is administered. In a patient with DIC accompanied by blood diseases showing a decrease level of the production of platelets, it is essential to replenish platelets by the administration of platelet concentrate. To a patient suffering from DIC with decreased blood fibrinogen, fresh frozen plasma (FFP) is transfused.
A disease condition designated microangiopathic hemolytic anemia (MAHA) is observed in TTP, as well as DIC or HUS. If many microthrombi are formed in blood vessels due to a particular cause, many portions of the microcirculation become narrow. Erythrocytes which forcibly have passed through these narrowed portions are mechanically broken, and hemolysis occurs. These processes are considered the mechanism of the development of MAHA. The main components of the microthrombi, which reduce the internal diameter of the vessels, are fibrin and platelets in DIC and TTP or HUS, respectively.
TTP was first reported in 1924 by Moschcowitz in the United States. TTP is a systemic severe disease which is caused by the clogging of arterioles with platelet aggregates (platelet thrombi), and characterized by the following symptoms: (1) thrombocytopenia (purpura is observed in the skin), (2) microangiopathic hemolytic anemia (caused by the breakdown of erythrocytes), (3) renal failures, (4) fever, and (5) neurologic disturbances.
As a factor of TTP, a cleaving protease specific to plasma vWF as a hemostatic factor (VWF-cleaving protease; VWF-CP), also known as ADAMTS13, was identified. It is known that the amount of ADAMTS13 is significantly lowered in patients with TTP, in comparison with healthy persons (for example, non-patent reference 1, non-patent reference 2, or patent reference 1). If ADAMTS13 is deficient or reduced, unusually large vWF multimers (UL-vWFMs) released from vascular endothelial cells are not cleaved, and an excessive platelet aggregation occurs due to a high shear stress caused in the microcirculation or the like, and as a result, blood vessels are occluded with thrombi.
For example, patent reference 2 discloses a method of detecting thrombosis or the degree of thrombophilia, characterized by measuring ADAMTS13, and acute or chronic myeloid leukemia, acute promyelocytic leukemia, systemic lupus erythematosus, pulmonary embolism, cerebral infarction, veno-occlusive disease, acute lymphocytic leukemia, thrombotic microangiopathy, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, and deep vein thrombosis are used to exemplify thrombosis. Patent reference 3 discloses a method of detecting platelet thrombosis or organ failure in a patient suffering from DIC or systemic inflammatory response syndrome (SIRS), comprising analyzing ADAMTS13 and/or a cleaving factor thereof (for example, elastase, plasmin, or thrombin).
Further, atypical TTP having a slightly decreased or normal ADAMTS13 activity is known. A variety of causes for atypical TTP were reported, and include congenital factors and acquired factors. An abnormality of genes, such as a plasma Factor H having a complement regulatory activity, or vascular endothelial cell transmembrane protein CD46, were reported as the congenital factors.
TTP is an extremely rare disease, which is generally caused by acquired factors, but rare cases caused by congenital factors are known as described below.
Clinical symptoms in TTP include, for example, diarrhea, abdominal pain, and blood stool due to ischemic enteritis, neurological symptoms such as convulsion and visual disorder, and renal disorder. As laboratory findings, various changes accompanied by hemolysis are observed, for examples, peripheral blood erythrocytes broken by thrombus formation, anemia, decreased platelets, serum LDH (lactate dehydrogenase), elevated indirect bilirubin, or decreased haptoglobin. Elevated serum creatine is observed in patients with renal disorder.
In a treatment for congenital TTP widely used at present, fresh frozen plasma (FFP) is transfused every two or three weeks to replenish ADAMTS13 and maintain a platelet count, i.e., to prevent the development of TTP. A transfusion of platelets is contraindicated in patients with congenital TTP. In approximately one-third of all patients with acquired TTP, an ADAMTS13 activity is remarkably decreased, and almost all the cases are positive for an autoantibody specific to ADAMTS13. Therefore, the administration of FFP alone is insufficient to treat acquired and idiopathic TTP, and a plasma exchange (PE) is the first option. The PE is often carried out together with steroids or a steroid pulse therapy. Of course, a platelet transfusion before the PE is contraindicated. The effects of PE are summarized as 1) the replenishment of ADAMTS13, 2) the removal of an ADAMTS13 inhibitor, 3) the removal of UL-vWFM, and 4) the replenishment of normal vWF necessary for hemostasis. The use of an immunosuppressant, such as vincristine or endoxan, or splenectomy should be considered for intractable cases or repetitive cases. The mortality rate before the introduction of the PE or the FFP transfusion therapy was more than 80%, and the prognosis was very poor. However, such an introduction or a combination thereof with an antiplatelet therapy has remarkably improved the prognosis, so that the survival rate becomes approximately 90% or more now. However, many refractory cases and recurrent cases are known, and there remain problems to be solved. Further, advanced TTP is refractory and has a poor prognosis, and thus, an early diagnosis and an early treatment are necessary.    [non-patent reference 1] Zheng X. et al., J. Biol. Chem., (U.S.A.), 2001, vol. 276, p. 41059-41063    [non-patent reference 2] Furlan M. et al., Blood, (U.S.A.), 1997, vol. 89, p. 3097-3103    [patent reference 1] WO 00/50904    [patent reference 2] WO 2005/062054    [patent reference 3] WO 2006/049300